For example, the new study found that, when used in high doses, diclofenac increases the risk of cardiovascular disease, on average causing about 3 extra heart attacks a year in every 1000 patients treated, one of which would be fatal.

The study authors emphasize the risks are mainly relevant to people with arthritis who need to take high doses over a long period. A short course of lower-dose NSAIDs purchased without a prescription, for example for a muscle sprain, is not likely to be hazardous.

The study also found that high doses of diclofenac increased the risk of a major vascular event (heart attack, stroke, or dying from cardiovascular disease) by around one third. Most of this additional risk was due to an increased risk of heart attacks. In contrast, high doses of naproxen did not appear to increase the risk of heart attacks. The researchers say this may be because naproxen also has protective effects that balance out any extra risk of heart attacks.

Concerns about the possible heart risks of NSAIDs, many of which have been on the market for several decades, arose after randomized trials showed that a newer class of NSAIDs known as COX-2 inhibitors or coxibs increased the risk of heart attacks.

"The complicated NSAID story, which has unfolded over a decade, reveals the predictive power of integrating data drawn from detailed studies of drug action in small numbers of humans, genetically and pharmacologically manipulated animal models, observational studies and randomized trials and from human genetics,” said FitzGerald. "It is remarkable how so many of our predictions from human and animal studies - the similar thrombotic risk from celecoxib and rofecoxib, the diverse cardiovascular risks of diclofenac and naproxen, the pattern of NSAID induced heart failure - are borne out by this analysis.

“A few uncertainties remain. We did not have much data with ibuprofen and it is unclear whether the small signal of risk relates to ibuprofen or its ability to undermine the benefit from concomitant low-dose aspirin. Also the failure to provide data on the trials of valdecoxib has limited our ability to relate drug-related risk to previous underlying risk of cardiovascular disease, which was especially high in the trials of this agent.

Despite these limitations, we now have perhaps the most diversified set of information on any aspect of any drug action, and it is a remarkable how faithfully it integrates mechanism with clinical consequence - a true example of translational therapeutics.”

The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 18 years, according toU.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $373 million awarded in the 2015 fiscal year.

The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center -- which are recognized as one of the nation's top "Honor Roll" hospitals byU.S. News & World Report-- Chester County Hospital; Lancaster General Health; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Chestnut Hill Hospital and Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2015, Penn Medicine provided $253.3 million to benefit our community.